Bach1 modulates heme oxygenase-1 expression in the neonatal mouse lung.
Heme oxygenase-1 (HO-1), the rate-limiting enzyme of heme degradation and antioxidant defense protein, is induced in the lungs of animals exposed to hyperoxia. However, high levels of HO-1 expression may be deleterious, thus necessitating tight regulation. Previous reports show maturational differences in rat HO-1 regulation in hyperoxia, as newborns do not up-regulate HO-1mRNA compared with adults. To better understand the differential response of lung HO-1 to hyperoxia, we exposed newborn and adult mice to >95% oxygen. The newborn lungs had reduced HO-1 mRNA induction compared with adults and newborn transgenic mice over-expressing luciferase driven by the 15 kb HO-1 promoter (HO-1/Luc Tg) had less increased light emission in hyperoxia compared with adults. Compared with adults, levels of the repressor of HO-1 transcription, Bach1, were higher in the neonatal lung as was nuclear protein-DNA binding to the antioxidant response element (ARE) from HO-1. Furthermore, at baseline and in hyperoxia, chromatin immunoprecipitation (ChIP) revealed increased Bach1 binding to the HO-1 distal enhancers (DEs) in the neonates compared with adults. These data suggest that elevated levels of Bach1 may help to limit HO-1 induction in the newborn at baseline and in response to oxidative stress.
Kassovska-Bratinova
Sacha
S
Division of Neonatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Yang
Guang
G
Igarashi
Kazuhiko
K
Dennery
Phyllis A
PA
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D051547:Heme Oxygenase-1 / Q000235:genetics*; D018496:Hyperoxia / Q000201:enzymology* / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D008168:Lung / Q000201:enzymology*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D013997:Time Factors; D014158:Transcription, Genetic
D000975:Antioxidants; C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D008565:Membrane Proteins; D012333:RNA, Messenger; D008156:Luciferases; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse